Since the beginning of optogenetics, the technique has been more effective at switching neurons on than off — but not anymore. Almost a decade ago, Dr. Karl Deisseroth discovered optogenetics, in which light-activated opsins from algae pass electrical current into neurons to control brain circuitry. Recently, his team at Stanford University has re-engineered the light-sensitive proteins to enable more efficient regulation of the cells’ “off” switches. Those switches were more limited in first-generation optogenetics because of channelrhodopsin’s weak inhibitory pump, which could move only one ion per photon of light, as opposed to the efficient excitatory channel that switched cells on. The inhibitory and excitatory switches were comparable in power to a squirt gun and a garden hose, respectively, according to Deisseroth, a professor of bioengineering, psychiatry and behavioral sciences at Stanford and lead researcher in this work. Channelrhodopsin, an excitatory cellular channel taken from algae and commonly used in optogenetics, has been transformed into a powerful inhibitory channel, allowing neurons to be switched off as well as on. Courtesy of Stanford University. “This is something we and others in the field have sought for a very long time,” he said. “What had been working through a weak pump can now work through a highly responsive channel with many orders of magnitude and more impact on cell function.” To turn channelrhodopsin into an effective inhibitory channel, the researchers needed to create a lining in the central pore. To do this, they re-engineered the excitatory channel, changing nine of its approximately 300 amino acids. The researchers found that when trigged by light, the protein opened a channel that was lined by more positively charged amino acids, and in turn attracted a flow of negative (chloride) ions to inhibit activity. By changing a 10th amino acid, they were able to keep the new negative channel (which they called SwiChR) open, which made it more like the positive channel and created a more light-sensitive inhibitory channel opsin. With this advance, the researchers expect the opportunities for optogenetics to expand. “[The recent development] creates a powerful tool that allows neuroscientists to apply a brake in any specific circuit with millisecond precision, beyond the power of any existing technology,” said Dr. Thomas Insel, director of the National Institute of Mental Health. “This will be vital for understanding brain circuits involved in behavior, thinking and emotion.” In addition, Deisseroth and colleagues have found that the stronger the inhibition is, the less light is required to achieve a desired effect, which could lead to therapeutic applications including pain management. The study was funded by the National Institute of Mental Health and the National Institute on Drug Abuse. The research is published in Science (doi: 10.1126/science.1252367). For more information, visit: www.stanford.edu